The risk of respiratory diseases increases significantly with advancing age. Elderly people are more prone to lung infections such as influenza and pneumonia and chronic illnesses such as asthma and obstructive pulmonary disease. The underlying mechanisms are not well understood. Airways are continuously being exposed to a wide variety of inhaled antigens majority of which are harmless. Dendritic cells (DCs) are key innate immune cells which are critical for initiation and generation of an effective immune response against invading pathogens as well as for maintaining tolerance against harmless inhaled antigens. Vitamin A metabolite, Retinoic acid (RA) plays a major role in inducing tolerance in respiratory DCs. Our preliminary data suggests that DCs from aged subjects are impaired in their response to retinoic acid resulting in loss of tolerance. Furthermore, aged DCs also affect the functions of airway epithelial cells to induce the secretion of various chemokines such as CXCL-10, CCL-26, and CCL-20 which can attract other cells into the airways and enhance inflammation. Therefore, we hypothesize that DCs from aged are impaired in their capacity to maintain tolerance at the respiratory surfaces which results in chronic inflammation and remodeling of the airways and increases the susceptibility of the elderly to respiratory illnesses. Our specific aims for the proposal are -1) to investigate the mechanisms responsible for impaired response of DCs from elderly to RA; 2) to determine the functional consequences of reduced RA metabolism in aged DCs; 3) to investigate the effect of altered RA response of aged DC on DC-epithelial cell crosstalk. Aged population is increasing worldwide and a better understanding of the mechanisms underlying the increased susceptibility of the elderly to respiratory diseases is required for design of novel and more effective treatment.